TY - JOUR
T1 - Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology
AU - Reichenstein, Irit
AU - Eitan, Chen
AU - Diaz-Garcia, Sandra
AU - Haim, Guy
AU - Magen, Iddo
AU - Siany, Aviad
AU - Hoye, Mariah L.
AU - Rivkin, Natali
AU - Olender, Tsviya
AU - Toth, Beata
AU - Ravid, Revital
AU - Mandelbaum, Amitai D.
AU - Yanowski, Eran
AU - Liang, Jing
AU - Rymer, Jeffrey K.
AU - Levy, Rivka
AU - Beck, Gilad
AU - Ainbinder, Elena
AU - Farhan, Sali M.K.
AU - Lennox, Kimberly A.
AU - Bode, Nicole M.
AU - Behlke, Mark A.
AU - Möller, Thomas
AU - Saxena, Smita
AU - Moreno, Cristiane A.M.
AU - Costaguta, Giancarlo
AU - van Eijk, Kristel R.
AU - Phatnani, Hemali
AU - Al-Chalabi, Ammar
AU - Başak, A. Nazli
AU - van den Berg, Leonard H.
AU - Hardiman, Orla
AU - Landers, John E.
AU - Mora, Jesus S.
AU - Morrison, Karen E.
AU - Shaw, Pamela J.
AU - Veldink, Jan H.
AU - Pfaff, Samuel L.
AU - Yizhar, Ofer
AU - Gross, Christina
AU - Brown, Robert H.
AU - Ravits, John M.
AU - Harms, Matthew B.
AU - Miller, Timothy M.
AU - Hornstein, Eran
N1 - Funding Information:
The work was funded by Target ALS (118945 to E.H., J.M.R., and S.L.P.), Legacy Heritage Fund, Bruno and Ilse Frick Foundation for Research on ALS, Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE), and Minna-James-Heineman Stiftung through Minerva. The research leading to these results has received funding to E.H. from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement number 617351; the Israel Science Foundation; the ALS-Therapy Alliance; the AFM Telethon (20576 to E.H.); the Motor Neuron Disease Association (United Kingdom); the Thierry Latran Foundation for ALS research; the ERA-Net for Research Programmes on Rare Diseases (FP7); A. Alfred Taubman through IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine, Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); M. Halphen; and Estates of F. Sherr, L. Asseof, L. Fulop, E. and J. Moravitz. S.M.K.F. was supported by the ALS Canada Tim E. Noël Postdoctoral Fellowship. C.E. and I.M. were supported by scholarship from Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE). Work at the C. Gross laboratory was supported by NIH grant R01NS092705 (to C.G.). Work at the T. M. Miller laboratory was supported by grants from Project5 for ALS, Target ALS, the National Institute of Neurological Disorders and Stroke (R01NS078398 to T.M.M. and F31NS092340 to M.L.H. and T.M.M.), the Robert Packard Center for ALS Research, the University of Missouri Spinal Cord Injury/Disease Research Program, and the Hope Center for Neurological Disorders. Work at the M. B. Harms laboratory was funded by grants from ALS Association and Biogen. R.H.B. was funded by ALS Association, ALS Finding a Cure, Angel Fund, ALS-One, Cellucci Fund, and NIH grants (R01 NS104022, R01 NS073873, and NS111990-01 to R.H.B.). A.A.-C. was supported through the following funding organizations under the aegis of JPND [www.jpnd.eu; United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1)] and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King’s College London. A.N.B. was supported by the Suna and Inan Kirac Foundation. J.E.L. was supported by the NIH/NINDS (R01 NS073873). H.P. was supported by a grant from the ALS Association.
Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2019/12/18
Y1 - 2019/12/18
N2 - Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.
AB - Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease.
UR - http://www.scopus.com/inward/record.url?scp=85080837788&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aav5264
DO - 10.1126/scitranslmed.aav5264
M3 - Article
C2 - 31852800
AN - SCOPUS:85080837788
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 523
M1 - eaav5264
ER -